Abstract
In mammals, creatine is taken up from the diet and can be synthesized endogenously by a two-step mechanism involving the enzymes arginine:glycine amidinotransferase (AGAT) and guanidinoacetate methyltransferase (GAMT). Creatine (Cr) is taken up by cells through a specific transporter, CT1. While the major part of endogenous synthesis of Cr is thought to occur in kidney, pancreas and liver, the brain widely expresses AGAT, GAMT and CT1, both during development and in adulthood. The adult central nervous system (CNS) has a limited capacity to take up Cr from periphery, and seems to rely more on its endogenous Cr synthesis. In contrast, the embryonic CNS might be more dependent on Cr supply from periphery than on endogenous synthesis. This review will focus on the expression and function of AGAT, GAMT and CT1 in the mammalian CNS, both during development and in adulthood. Emphasis will also be placed on their specific roles in the different cell types of the brain, to analyze which brain cells are responsible for the CNS capacity of (i) endogenous Cr synthesis and (ii) Cr uptake from the periphery, and which brain cells are the main Cr consumers. The potential role of CT1 as guanidinoacetate transporter between “AGAT-only” and “GAMT-only” expressing cells will also be explored
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Acosta, M.L., Kalloniatis, M., and Christie, D.L., 2005, Creatine transporter localization in developing and adult retina: importance of creatine to retinal function. Am. J. Physiol. Cell Physiol. 289: C1015–C1023.
Almeida, L.S., Salomons, G.S., Hogenboom, F., Jakobs, C., and Schoffelmeer, A.N., 2006, Exocytotic release of creatine in rat brain. Synapse 60: 118–123.
Anselm, I.M., Alkuraya, F.S., Salomons, G.S., Jakobs, C., Fulton, A.B., Mazumdar, M., Rivkin, M., Frye, R., Poussaint, T.Y., and Marsden, D., 2006, X-linked creatine transporter defect: a report on two unrelated boys with a severe clinical phenotype. J. Inherit. Metab. Dis. 29: 214–219.
Battini, R., Alessandri, M.G., Leuzzi, V., Moro, F., Tosetti, M., Bianchi, M.C., and Cioni, G., 2006, Arginine:glycine amidinotransferase (AGAT) deficiency in a newborn: early treatment can prevent phenotypic expression of the disease. J. Pediatr. 148: 828–830.
Battini, R., Leuzzi, V., Carducci, C., Tosetti, M., Bianchi, M.C., Item, C.B., Stöckler-Ipsiroglu, S., and Cioni, G., 2002, Creatine depletion in a new case with AGAT deficiency: clinical and genetic study in a large pedigree. Mol. Genet. Metab. 77: 326–331.
Bizzi, A., Bugiani, M., Salomons, G.S., Hunneman, D.H., Moroni, I., Estienne, M., Danesi, U., Jakobs, C., and Uziel, G., 2002, X-linked creatine deficiency syndrome: a novel mutation in creatine transporter gene SLC6A8. Ann. Neurol. 52: 227–231.
Braissant, O., Villard, A., Henry, H., Speer, O., Wallimann, T., and Bachmann, C., 2005a, Synthesis and transport of creatine in the central nervous system. In Clinical and molecular aspects of defects in creatine and polyol metabolism, Jakobs, C., and Stöckler-Ipsiroglu, S., eds. (SPS Verlagsgesellschaft, Heilbronn, Germany), pp. 49–63.
Braissant, O., Gotoh T., Loup, M., Mori M., and Bachmann, C., 2001a, Differential expression of the cationic amino acid transporter 2(B) in the adult rat brain. Mol. Brain Res. 91: 189–195.
Braissant, O., Gotoh, T., Loup, M., Mori, M., and Bachmann, C., 1999, L-arginine uptake, the citrulline-NO cycle and arginase II in the rat brain: an in situ hybridization study. Mol. Brain Res. 70: 231–241.
Braissant, O., Henry, H., Loup, M., Eilers, B., and Bachmann, C., 2001b, Endogenous synthesis and transport of creatine in the rat brain: an in situ hybridization study. Mol. Brain Res. 86: 193–201.
Braissant, O., Henry, H., Villard, A.M., Speer, O., Wallimann, T., and Bachmann, C., 2005b, Creatine synthesis and transport during rat embryogenesis: Spatiotemporal expression of AGAT, GAMT and CT1. BMC Dev. Biol. 5: 9.
Braissant, O., Henry, H., Villard, A.M., Zurich, M.G., Loup, M., Eilers, B., Parlascino, G., Matter, E., Boulat, O., Honegger, P., and Bachmann, C., 2002, Ammonium-induced impairment of axonal growth is prevented through glial creatine. J. Neurosci. 22: 9810–9820.
Cecil, K.M., Salomons, G.S., Ball, W.S., Jr., Wong, B., Chuck, G., Verhoeven, N.M., Jakobs, C., and DeGrauw, T.J., 2001, Irreversible brain creatine deficiency with elevated serum and urine creatine: a creatine transporter defect? Ann. Neurol. 49: 401–404.
Daly, M.M., 1985, Guanidinoacetate methyltransferase activity in tissues and cultured cells. Arch. Biochem. Biophys. 236: 576–584.
Davis, B.M., Miller, R.K., Brent, R.L., and Koszalka, T.R., 1978, Materno-fetal transport of creatine in the rat. Biol. Neonate 33: 43–54.
DeGrauw, T.J., Salomons, G.S., Cecil, K.M., Chuck, G., Newmeyer, A., Schapiro, M.B., and Jakobs, C., 2002, Congenital creatine transporter deficiency. Neuropediatrics 33: 232–238.
Dickmeis, T., Rastegar, S., Aanstad, P., Clark, M., Fischer, N., Plessy, C., Rosa, F., Korzh, V., and Strahle, U., 2001, Expression of brain subtype creatine kinase in the zebrafish embryo. Mech. Dev. 109: 409–412.
Dringen, R., Verleysdonk, S., Hamprecht, B., Willker, W., Leibfritz, D., and Brand, A., 1998, Metabolism of glycine in primary astroglial cells: synthesis of creatine, serine, and glutathione. J. Neurochem. 70: 835–840.
Dziegielewska, K.M., Ek, J., Habgood, M.D., and Saunders, N.R., 2001, Development of the choroid plexus. Microsc. Res. Tech. 52: 5–20.
Engelhardt, B., 2003, Development of the blood-brain barrier. Cell Tissue Res. 314: 119–129.
Galbraith, R.A., Furukawa, M., and Li, M., 2006, Possible role of creatine concentrations in the brain in regulating appetite and weight. Brain Res. 1101: 85–91.
Ganesan, V., Johnson, A., Connelly, A., Eckhardt, S., and Surtees, R.A., 1997, Guanidinoacetate methyltransferase deficiency: new clinical features. Pediatr. Neurol. 17: 155–157.
Guimbal, C. and Kilimann, M.W., 1993, A Na+-dependent creatine transporter in rabbit brain, muscle, heart, and kidney. cDNA cloning and functional expression. J. Biol. Chem. 268: 8418–8421.
Happe, H.K. and Murrin, L.C., 1995, In situ hybridization analysis of CHOT1, a creatine transporter, in the rat central nervous system. J. Comp. Neurol. 351: 94–103.
Hemmer, W., Zanolla, E., Furter-Graves, E.M., Eppenberger, H.M., and Wallimann, T., 1994, Creatine kinase isoenzymes in chicken cerebellum: specific localization of brain-type creatine kinase in Bergmann glial cells and muscle-type creatine kinase in Purkinje neurons. Eur. J. Neurosci. 6: 538–549.
Holtzman, D., McFarland, E., Moerland, T., Koutcher, J., Kushmerick, M.J., and Neuringer, L.J., 1989, Brain creatine phosphate and creatine kinase in mice fed an analogue of creatine. Brain Res. 483: 68–77.
Item, C.B., Stöckler-Ipsiroglu, S., Stromberger, C., Muhl, A., Alessandri, M.G., Bianchi, M.C., Tosetti, M., Fornai, F., and Cioni, G., 2001, Arginine:glycine amidinotransferase deficiency: the third inborn error of creatine metabolism in humans. Am. J. Hum. Genet. 69: 1127–1133.
Kaldis, P., Hemmer, W., Zanolla, E., Holtzman, D., and Wallimann, T., 1996, ‘Hot spots’ of creatine kinase localization in brain: cerebellum, hippocampus and choroid plexus. Dev. Neurosci. 18: 542–554.
Koszalka, T.R., Jensh, R.P., and Brent, R.L., 1975, Placental transport of creatine in the rat. Proc. Soc. Exp. Biol. Med. 148: 864–869.
Kreis, R., Hofmann, L., Kuhlmann, B., Boesch, C., Bossi, E., and Huppi, P.S., 2002, Brain metabolite composition during early human brain development as measured by quantitative in vivo 1H magnetic resonance spectroscopy. Magn. Reson. Med. 48: 949–958.
Lee, H., Kim, J.H., Chae, Y.J., Ogawa, H., Lee, M.H., and Gerton, G.L., 1998, Creatine synthesis and transport systems in the male rat reproductive tract. Biol. Reprod. 58: 1437–1444.
Lyons, G.E., Muhlebach, S., Moser, A., Masood, R., Paterson, B.M., Buckingham, M.E., and Perriard, J.C., 1991, Developmental regulation of creatine kinase gene expression by myogenic factors in embryonic mouse and chick skeletal muscle. Development 113: 1017–1029.
Mercimek-Mahmutoglu, S., Stoeckler-Ipsiroglu, S., Adami, A., Appleton, R., Araujo, H.C., Duran, M., Ensenauer, R., Fernandez-Alvarez, E., Garcia, P., Grolik, C., Item, C.B., Leuzzi, V., Marquardt, I., Muhl, A., Saelke-Kellermann, R.A., Salomons, G.S., Schulze, A., Surtees, R., van der Knaap, M.S., Vasconcelos, R., Verhoeven, N.M., Vilarinho, L., Wilichowski, E., and Jakobs, C., 2006, GAMT deficiency: features, treatment, and outcome in an inborn error of creatine synthesis. Neurology 67: 480–484.
Miller, T.J., Hanson, R.D., and Yancey, P.H., 2000, Developmental changes in organic osmolytes in prenatal and postnatal rat tissues. Comp. Biochem. Physiol. A Mol. Integr. Physiol. 125: 45–56.
Möller, A. and Hamprecht, B., 1989, Creatine transport in cultured cells of rat and mouse brain. J. Neurochem. 52: 544–550.
Nakashima, T., Tomi, M., Katayama, K., Tachikawa, M., Watanabe, M., Terasaki, T., and Hosoya, K., 2004, Blood-to-retina transport of creatine via creatine transporter (CRT) at the rat inner blood-retinal barrier. J. Neurochem. 89: 1454–1461.
Nakashima, T., Tomi, M., Tachikawa, M., Watanabe, M., Terasaki, T., and Hosoya, K., 2005, Evidence for creatine biosynthesis in Muller glia. GLIA 52: 47–52.
Neu, A., Neuhoff, H., Trube, G., Fehr, S., Ullrich, K., Roeper, J., and Isbrandt, D., 2002, Activation of GABAA receptors by guanidinoacetate: a novel pathophysiological mechanism. Neurobiol. Dis. 11: 298–307.
Ohtsuki, S., Tachikawa, M., Takanaga, H., Shimizu, H., Watanabe, M., Hosoya, K., and Terasaki, T., 2002, The blood-brain barrier creatine transporter is a major pathway for supplying creatine to the brain. J. Cereb. Blood Flow Metab. 22: 1327–1335.
Perasso, L., Cupello, A., Lunardi, G.L., Principato, C., Gandolfo, C., and Balestrino, M., 2003, Kinetics of creatine in blood and brain after intraperitoneal injection in the rat. Brain Res. 974: 37–42.
Pisano, J.J., Abraham, D., and Udenfriend, S., 1963, Biosynthesis and disposition of \UPgamma-guanidinobutyric acid in mammalian tissues. Arch. Biochem. Biophys. 100: 323–329.
Poo-Arguelles, P., Arias, A., Vilaseca, M.A., Ribes, A., Artuch, R., Sans-Fito, A., Moreno, A., Jakobs, C., and Salomons, G., 2006, X-Linked creatine transporter deficiency in two patients with severe mental retardation and autism. J. Inherit. Metab. Dis. 29: 220–223.
Salomons, G.S., van Dooren, S.J., Verhoeven, N.M., Cecil, K.M., Ball, W.S., Degrauw, TJ, and Jakobs, C., 2001, X-linked creatine-transporter gene (SLC6A8) defect: a new creatine-deficiency syndrome. Am. J. Hum. Genet. 68: 1497–1500.
Salomons, G.S., van Dooren, S.J., Verhoeven, N.M., Marsden, D., Schwartz, C., Cecil, K.M., DeGrauw, T.J., and Jakobs, C., 2003, X-linked creatine transporter defect: an overview. J. Inherit. Metab. Dis. 26: 309–318.
Saltarelli, M.D., Bauman, A.L., Moore, K.R., Bradley, C.C., and Blakely, R.D., 1996, Expression of the rat brain creatine transporter in situ and in transfected HeLa cells. Dev. Neurosci. 18: 524–534.
Sandell, L.L., Guan, X.J., Ingram, R., and Tilghman, S.M., 2003, Gatm, a creatine synthesis enzyme, is imprinted in mouse placenta. Proc. Natl. Acad. Sci. U. S. A. 100: 4622–4627.
Schloss, P., Mayser, W., and Betz, H., 1994, The putative rat choline transporter CHOT1 transports creatine and is highly expressed in neural and muscle-rich tissues. Biochem. Biophys. Res. Commun. 198: 637–645.
Schmidt, A., Marescau, B., Boehm, E.A., Renema, W.K., Peco, R., Das, A., Steinfeld, R., Chan, S., Wallis, J., Davidoff, M., Ullrich, K., Waldschutz, R., Heerschap, A., De Deyn, P.P., Neubauer, S., and Isbrandt, D., 2004, Severely altered guanidino compound levels, disturbed body weight homeostasis and impaired fertility in a mouse model of guanidinoacetate N-methyltransferase (GAMT) deficiency. Hum. Mol. Genet. 13: 905–921.
Schulze, A., 2003, Creatine deficiency syndromes. Mol. Cell. Biochem. 244: 143–150.
Schulze, A., Ebinger, F., Rating, D., and Mayatepek, E., 2001, Improving treatment of guanidinoacetate methyltransferase deficiency: reduction of guanidinoacetic acid in body fluids by arginine restriction and ornithine supplementation. Mol. Genet. Metab. 74: 413–419.
Schulze, A., Hess, T., Wevers, R., Mayatepek, E., Bachert, P., Marescau, B., Knopp, M.V., De Deyn, P.P., Bremer, H.J., and Rating, D., 1997, Creatine deficiency syndrome caused by guanidinoacetate methyltransferase deficiency: diagnostic tools for a new inborn error of metabolism. J. Pediatr. 131: 626–631.
Schulze, A., Hoffmann, G.F., Bachert, P., Kirsch, S., Salomons, G.S., Verhoeven, N.M., and Mayatepek, E., 2006, Presymptomatic treatment of neonatal guanidinoacetate methyltransferase deficiency 1. Neurology 67: 719–721.
Schulze, A., Mayatepek, E., Bachert, P., Marescau, B., De Deyn, P.P., and Rating, D., 1998, Therapeutic trial of arginine restriction in creatine deficiency syndrome. Eur. J. Pediatr. 157: 606–607.
Segal, M.B., 2000, The choroid plexuses and the barriers between the blood and the cerebrospinal fluid. Cell. Mol. Neurobiol. 20: 183–196.
Stöckler, S., Holzbach, U., Hanefeld, F., Marquardt, I., Helms, G., Requart, M., Hänicke, W., and Frahm, J., 1994, Creatine deficiency in the brain: a new, treatable inborn error of metabolism. Pediatr. Res. 36: 409–413.
Stöckler, S., Isbrandt, D., Hanefeld, F., Schmidt, B., and Von Figura, K., 1996, Guanidinoacetate methyltransferase deficiency: the first inborn error of creatine metabolism in man. Am. J. Hum. Genet. 58: 914–922.
Stockler, S., Schutz, P.W., and Salomons, G.S., 2007, Cerebral creatine deficiency syndromes: clinical aspects, treatment and pathophysiology. Subcell. Biochem. 46: 149–166.
Stromberger, C., Bodamer, O.A., and Stöckler-Ipsiroglu, S., 2003, Clinical characteristics and diagnostic clues in inborn errors of creatine metabolism. J. Inherit. Metab. Dis. 26: 299–308.
Sykut-Cegielska, J., Gradowska, W., Mercimek-Mahmutoglu, S., and Stockler-Ipsiroglu, S., 2004, Biochemical and clinical characteristics of creatine deficiency syndromes. Acta Biochim. Pol. 51: 875–882.
Tachikawa, M., Fukaya, M., Terasaki, T., Ohtsuki, S., and Watanabe, M., 2004, Distinct cellular expressions of creatine synthetic enzyme GAMT and creatine kinases uCK-Mi and CK-B suggest a novel neuron-glial relationship for brain energy homeostasis. Eur. J. Neurosci. 20: 144–160.
Van Pilsum, J.F., Stephens, G.C., and Taylor, D., 1972, Distribution of creatine, guanidinoacetate and enzymes for their biosynthesis in the animal kingdom. Implications for phylogeny. Biochem. J. 126: 325–345.
Walker, J.B., 1979, Creatine: biosynthesis, regulation, and function. Adv. Enzymol. Relat. Areas Mol. Biol. 50: 177–242.
Wallimann, T. and Hemmer, W., 1994, Creatine kinase in non-muscle tissues and cells. Mol. Cell. Biochem. 133–134: 193–220.
Wallimann, T., Wyss, M., Brdiczka, D., Nicolay, K., and Eppenberger, H.M., 1992, Intracellular compartmentation, structure and function of creatine kinase isoenzymes in tissues with high and fluctuating energy demands: the ‘phosphocreatine circuit’ for cellular energy homeostasis. Biochem. J. 281: 21–40.
Wang, Y. and Li, S.J., 1998, Differentiation of metabolic concentrations between gray matter and white matter of human brain by in vivo 1H magnetic resonance spectroscopy. Magn. Reson. Med. 39: 28–33.
Wang, Y.E., Esbensen, P., and Bentley, D., 1998, Arginine kinase expression and localization in growth cone migration. J. Neurosci. 18: 987–998.
Whittingham, T.S., Douglas, A., and Holtzman, D., 1995, Creatine and nucleoside triphosphates in rat cerebral gray and white matter. Metab. Brain Dis. 10: 347–352.
Wyss, M. and Kaddurah-Daouk, R., 2000, Creatine and creatinine metabolism. Physiol. Rev. 80: 1107–1213.
Zugno, A.I., Scherer, E.B., Schuck, P.F., Oliveira, D.L., Wofchuk, S., Wannmacher, C.M., Wajner, M.,and Wyse, A.T., 2006, Intrastriatal administration of guanidinoacetate inhibits Na+, K+-ATPase and creatine kinase activities in rat striatum. Metab. Brain Dis. 21: 41–50.
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Braissant, O., Bachmann, C., Henry, H. (2007). Expression and Function of Agat, Gamt and CT1 in the Mammalian Brain. In: Salomons, G.S., Wyss, M. (eds) Creatine and Creatine Kinase in Health and Disease. Subcellular Biochemistry, vol 46. Springer, Dordrecht. https://doi.org/10.1007/978-1-4020-6486-9_4
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